There is a critical need for therapeutics to control the damage to the brain that accompanies traumatic brain injury (TBI). Oxidative stress and neuronal loss are components of the ischemic cascade that ensues immediately after a TBI. Centaur's proprietary compounds have already demonstrated their ability to protect the brain from ischemic damage when administered after a cerebral stroke. One of these compounds is in human clinical trials for stroke. (Because of restrictions in our corporate partner relationship with Astra AB, this compound cannot be pursued for other indications.) The experiments proposed in this grant application will use in vitro screens of hypoxia/reoxygenation to select compounds for evaluation in the controlled cortical impact (CCI) rat models of TBI. In vivo cognitive studies will be combined with histopathology to measure drug efficacy. Medicinal chemistry and structure/activity relationships will be applied to the selection of compounds for in vitro screening. These experiments will set the stage for the Phase II evaluations of mechanisms of action, structure/activity relationships, and the synthesis of compounds designed to have the appropriate balance of physical and biological properties for the treatment of TBI. PROPOSED COMMERCIAL APPLICATIONS: There is critical need for the development of effective clinical treatment for traumatic brain injury (TBI). TBI is the leading cause of death and disability in young adults. Mortality in severe brain injury approaches 50% and there are an estimated 1.5 million hospitalized cases in the industrialized world. At an approximate treatment cost of $3,000 per patient, the world market for TBI is $4.5 billion. Therapeutic interventions are currently limited to general supportive measures and to those focused on reducing intracranial pressure. Any therapeutic that could limit TBI damage would have widespread medical and commercial appeal. Centaur has nitrone related therapeutics (NRTs) that are efficacious in pilot TBI models and in animal models of stroke. NRTs are also extremely safe by comparison to other therapeutics under development. Given their wide margin of safety, these compounds have a high probability of success in TBI clinical trials and potentially represent the first effective TBI therapy.